Antibody-Mediated Rejection in Lung Transplantation: Clinical Outcomes and Donor-Specific Antibody Characteristics.

In the context of lung transplant (LT), because of diagnostic difficulties, antibody-mediated rejection (AMR) remains a matter of debate. We retrospectively analyzed an LT cohort at Foch Hospital to demonstrate the impact of AMR on LT prognosis. AMR diagnosis requires association of clinical symptoms, donor-specific antibodies (DSAs), and C4d(+) staining and/or histological patterns consistent with AMR. Prospective categorization split patients into four groups: (i) DSA positive, AMR positive (DSA(pos) AMR(pos) ); (ii) DSA positive, AMR negative (DSA(pos) AMR(neg) ); (iii) DSA limited, AMR negative (DSA(Lim) ; equal to one specificity, with mean fluorescence intensity of 500-1000 once); and (iv) DSA negative, AMR negative (DSA(neg) ). AMR treatment consisted of a combination of plasmapheresis, intravenous immunoglobulin and rituximab. Among 206 transplanted patients, 10.7% were DSA(pos) AMR(pos) (n = 22), 40.3% were DSA(pos) AMR(neg) (n = 84), 6% were DSA(Lim) (n = 13) and 43% were DSA(neg) (n = 88). Analysis of acute cellular rejection at month 12 showed higher cumulative numbers (mean plus or minus standard deviation) in the DSA(pos) AMR(pos) group (2.1 ± 1.7) compared with DSA(pos) AMR(neg) (1 ± 1.2), DSA(Lim) (0.75 ± 1), and DSA(neg) (0.7 ± 1.23) groups. Multivariate analysis demonstrated AMR as a risk factor for chronic lung allograft dysfunction (hazard ratio [HR] 8.7) and graft loss (HR 7.56) for DSA(pos) AMR(pos) patients. Our results show a negative impact of AMR on LT clinical course and advocate for an early active diagnostic approach and evaluation of therapeutic strategies to improve prognosis.

[Updated indications and contraindications in 2022 for lung transplantation in France]. / Transplantation pulmonaire en France : actualisation des indications et contre-indications en 2022.

Lung transplantation (LTx) is the last-resort treatment for end-stage respiratory insufficiency, whatever its origin, and represents a steadily expanding field of endeavor. Major developments have been impelled over the years by painstaking efforts at LTx centers to improve donor and recipient selection, and multifaceted attempts have been made to meet the challenges raised by surgical management, perioperative care, and long-term medical complications. The number of procedures has increased, leading to improved post-LTx prognosis. One consequence of these multiple developments has been a pruning away of contraindications over time, which has, in some ways, complicated the patient selection process. With these considerations in mind, the Francophone Pulmonology Society (Société de Pneumology de Langue Française [SPLF]) has set up a task force to produce up-to-date working guidelines designed to assist pulmonologists in managing end-stage respiratory insufficiency, determining which patients may be eligible for LTx, and appropriately timing LTx-center referral. The task force has examined the most recent literature and evaluated the risk factors that continue to limit patient survival after LTx. Ideally, the objectives of LTx are to prolong life while improving quality of life. The guidelines developed by the task force apply to a limited resource and are consistent with the ethical principles described below.

Non-classic cystic fibrosis associated with D1152H CFTR mutation.

BACKGROUND: Limited knowledge exists on phenotypes associated with the D1152H cystic fibrosis transmembrane conductance regulator (CFTR) mutation. METHODS: Subjects with a D1152H allele in trans with another CFTR mutation were identified using the French Cystic Fibrosis Registry. Phenotypic characteristics were compared with those of pancreatic insufficient (PI) and pancreatic sufficient (PS) cystic fibrosis (CF) subjects in the Registry (CF cohort). RESULTS: Forty-two subjects with D1152H alleles were identified. Features leading to diagnosis included chronic sinopulmonary disease (n = 25), congenital absence of the vas deferens (n = 11), systematic neonatal screening (n = 4), and genetic counseling (n = 2). Median age at diagnosis was 33 [interquartile range (IQR, 24-41)] years in D1152H subjects. Median sweat chloride concentrations were 43.5 (39-63) mmol/l in D1152H subjects and were markedly lower than in PI and PS CF subjects (p < 0.05). Bronchiectasis was present in 67% of D1152H subjects, but Pseudomonas aeruginosa colonization and pancreatic insufficiency were present in <30% of subjects. Estimated rates of decline in forced expiratory volume in 1 s (FEV(1)) were lower in D1152H subjects vs PI CF subjects (p < 0.05). None of the D1152H subjects identified since 1999 had died or required lung transplantation. CONCLUSIONS: When present in trans with a CF-causing mutation, D1152H causes significant pulmonary disease, but all subjects had prolonged survival.

Severe Aspergillus endocarditis in a lung transplant recipient with a five-year survival.

We report the case of a patient with cystic fibrosis who underwent lung transplant and developed Aspergillus endocarditis and cutaneous relapse. Long-term survival was achieved with surgical and prolonged antifungal treatment. This case report emphasizes the recommendation of life-long antifungal treatment in transplant recipients who survive an episode of fungal endocarditis.

Provision of information on transplantation to cystic fibrosis patients and their relatives: Overview of French practices and recommendations.

BACKGROUND: How health-care professionals inform cystic fibrosis patients and their relatives about transplantation is not well known. Such information may not be provided in a timely or satisfactory manner. We conducted a survey about patient information practices among professionals from all French cystic fibrosis centers and transplant centers, to determine how they might be improved. METHODS: This was a national, retrospective, multicenter, descriptive assessment of practices involving health-care professionals, transplant recipients and their relatives, and peer patients who are themselves transplant recipients. Questionnaires were developed by the French working group on cystic fibrosis patient education (GETHEM: Groupe éducation thérapeutique et mucoviscidose). At the end of the questionnaires, respondents were invited to suggest ways to improve the current process. RESULTS: In all, 216 professionals, 55 patients, 30 relatives of these patients, and 17 peer patients responded to the questionnaires, which addressed topics in chronological order, from neonatal screening or later diagnosis of the illness to the time of the transplant, if one was performed. CONCLUSIONS: Study findings have allowed us to draft nine recommendations for professionals to improve patient information practices. A booklet now being prepared aims to facilitate the process for professionals, and e-learning modules are also forthcoming.

The alpha subunit of the GTP binding protein Gk opens atrial potassium channels.

Guanine nucleotide binding (G) proteins (subunit composition alpha beta gamma) dissociate on activation with guanosine triphosphate (GTP) analogs and magnesium to give alpha-guanine nucleotide complexes and free beta gamma subunits. Whether the opening of potassium channels by the recently described Gk in isolated membrane patches from mammalian atrial myocytes was mediated by the alpha k subunit or beta gamma dimer was tested. The alpha k subunit was found to be active, while the beta gamma dimer was inactive in stimulating potassium channel activity. Thus, Gk resembles Gs, the stimulatory regulatory component of adenylyl cyclase, and transducin, the regulatory component of the visual system, in that it regulates its effector function--the activity of the ligand-gated potassium channel--through its guanine nucleotide binding subunit.

Clinical outcome following lung transplantation in patients with cystic fibrosis colonised with Burkholderia cepacia complex: results from two French centres.

BACKGROUND: Infection with Burkholderia cepacia complex (BCC) is a life threatening complication of cystic fibrosis (CF), often seen as a contraindication for lung transplantation. METHODS: A long term retrospective study was conducted of all patients with CF undergoing lung transplants from January 1990 to October 2006 in two French centres allowing transplantation in patients colonised with BCC. RESULTS: 22 of the 247 lung transplant patients with CF were infected with BCC (B. cenocepacia genomovar III (n = 8), B. multivorans genomovar II (n = 11), B. vietnamiensis genomovar V (n = 2) and B. stabilis genomovar IV (n = 1)). BCC colonisation was not associated with any significant excess mortality (HR 1.5, 95% CI 0.7 to 3.2; p = 0.58). However, early mortality rates tended to be higher in the BCC group than in the non-BCC group (3 month survival: 85% vs 95%, respectively; log rank p = 0.05). Univariate analysis showed that the risk of death was significantly higher for the eight patients infected with B. cenocepacia than for the other 14 colonised patients (HR 3.2, 95% CI 1.1 to 5.9; p = 0.04). None of the other risk factors tested-primary graft failure, late extubation, septicaemia-had a significant effect. The 5 year cumulative incidence rate of bronchiolitis obliterans syndrome was not significantly higher in the BCC group than in the non-BCC group (38% vs 24%, respectively; p = 0.35). CONCLUSION: Our results suggest that BCC infection with a non-genomovar III organism may not be associated with excess mortality after lung transplantation in patients with CF and should not be seen as sufficient reason to exclude lung transplantation. However, colonisation with B. cenocepacia remains potentially detrimental.

Adenosine diphosphate ribosylation of G proteins by pertussis and cholera toxin in isolated membranes. Different requirements for and effects of guanine nucleotides and Mg2+.

ADP ribosylation of membranes by pertussis toxin (PT) and cholera toxin (CT) was studied as a function of addition of ATP, various guanine nucleotides, Mg2+, and inorganic phosphate (Pi). ADP ribosylation of a 40 kilodalton (kDa) band by PT is markedly enhanced by ATP and GTP and is strongly inhibited by Pi or Mg2+. GTP analogs (GTP gamma S and GMP-adenyl-5'-yl imidodiphosphate) were less effective. In contrast, ADP ribosylation of two substrates for CT (of 42 and 50 kDa) is stimulated by Pi, Mg2+, and GTP or GTP analogs such as GTP gamma S, but is unaffected by ATP. These stimulatory conditions correlate well with GTP-mediated activation of stimulated nucleotide-binding regulatory component of adenyl cyclase. Optimal conditions for ADP ribosylation by PT do not correlate simply with conditions thought to lead to stabilization of an inactive form of inhibitory nucleotide-binding regulatory component of adenyl cyclase (Gi) or Gi-like protein; rather, the data suggest the involvement of both a stimulatory nucleotide site on PT (positively affected by either ATP or GTP) and a stabilizing site on the PT substrate (affected by GDP, GDP beta S, or GTP). Treatment of membranes with Lubrol PX increased ADP ribosylation by PT by as much as 25- to 30-fold, but inhibited the action of CT. Using defined conditions for ADP ribosylation by PT and CT, distinct labeling patterns were observed in thyroid, brain, corpus luteum, liver, heart, and erythrocytes membranes. All membranes were more intensely labeled by PT rather than CT.

[The management of lung transplantation candidates. A case series]. / Préparation des insuffisants respiratoires à la transplantation. Un état des lieux.

INTRODUCTION: Lung transplantation (LT) is associated with an increased risk of infection, cancer, chronic renal failure, cardiovascular disease and osteoporosis. Some risk factors precede transplantation and could benefit for early diagnosis and optimised care. METHODS: The incidence of comorbidities and their treatment before referral were assessed in 157 consecutive lung transplant candidates between 2008 and 2011. RESULTS: The median age was 37years [25; 51]. Fifty-six percent had a body mass index below 19kg/m(2). In the COPD group, only 50 % had undergone a pulmonary rehabilitation program in the preceding 2 years. Osteoporosis was present in 42 %, of whom 36 % were on bisphophonate therapy. Vitamin D deficiency was present in 65 %. Previously undiagnosed cardiovascular risk factors were discovered during LT assessment: hypertension in one patient, hypercholesterolemia in 6 % and diabetes in 4 %. Poor dental condition necessitating extractions were found in 41 % of patients. Protective anti-HBs antibodies levels were present in 50 % of the patients at the time of referral. CONCLUSION: The assessment and early treatment of nutritional disorders, osteoporosis and risk factors for infection as well as addressing associated cardiovascular risk factors should be optimised in the care of patients with chronic respiratory insufficiency. The potential for becoming a lung transplant candidate in the future should be kept in mind early in the global management of those patients.

Hormonal regulation of pituitary GH3 cell K+ channels by Gk is mediated by its alpha-subunit.

The resolved alpha-GTP gamma S (alpha*) and beta gamma-subunits of human erythrocyte Gk, the stimulatory regulatory component of hormone-responsive K+ channels, were tested for their potential stimulatory activities on the K+ channel of the endocrine GH3 cell. Concentrations as low as 0.5 pM alpha k* consistently activated K+ channels in isolated membrane patches, and saturating effects were obtained with 50 pM alpha k*. In contrast 2000-4000 pM beta gamma was without effect. We conclude that Gk acts on K+ channels through its alpha-subunit in a manner akin to that of Gs acting on adenylyl cyclase and transducin acting on cGMP-specific phosphodiesterase of photo-receptor cells.

Increased endothelin-1 associated with bacterial infection in lung transplant recipients.

BACKGROUND: Endothelin-1 (ET-1) has fibrogenic and inflammatory properties. Its pathogenic role in pulmonary fibrosis and certain inflammatory airway diseases is now well known. Its production is, in part, triggered by infectious processes. Episodes of infection are suspected to be involved in the development of bronchiolitis obliterans syndrome (BOS), which is the main feature of chronic lung rejection and the major factor limiting the long-term survival of transplanted patients. We postulated that ET-1 is upregulated during infectious complications arising from the graft and that this could partly explain the remodeling of airway structures observed in BOS. We, therefore, set up this study to assess ET-1 expression in relation to complications of the graft in human lung transplant recipients. METHODS: ET-1 mRNA was quantified by reverse transcription-competitive polymerase chain reaction in cells from 119 samples of bronchoalveolar lavage (BAL) fluid from 17 lung transplant recipients. ET-1 and big ET-1 proteins were assessed in BAL cell culture supernatants by enzyme immunoassay. Transbronchial biopsies (n=21) were stained immunohistochemically for ET-1 receptors. RESULTS: Episodes of bacterial infection strongly correlated with increased ET-1 mRNA and protein expression. ET-1 receptors were also upregulated during these episodes, especially on endothelial and smooth muscle cells. Five of the seven patients with the highest ET-1 levels subsequently developed BOS. CONCLUSIONS: These results raise the possibility that ET-1, part of whose production is triggered by infectious postgraft complications, might play a role in the development of BOS through its potential effects on airway remodeling.

Predictive value of cytomegalovirus DNA detection by polymerase chain reaction in blood and bronchoalveolar lavage in lung transplant patients.

BACKGROUND: Despite promising results, the efficacy of polymerase chain reaction (PCR) for clinical management of cytomegalovirus (CMV) infection in transplanted patients is still controversial. METHODS: A prospective study of CMV detection, with concurrent shell vial cultures and PCR in blood and bronchoalveolar lavage (BAL), was conducted in 13 lung transplant recipients, monitored for 15 months (range: 1-42 months). CMV DNA was detected by PCR amplification of a 406-bp fragment in the Us region and a 290-bp fragment in the immediate early region of the viral genome. RESULTS: When comparing PCR to viral culture, the sensitivity and specificity of CMV DNA detection were 100% and 65.7% in blood (n=122) and 100% and 75% in BAL (n=104). The positive and negative predictive values of PCR for a forthcoming diagnosis of CMV infection were 50% and 97% in blood, and 67% and 85% in BAL. Seventeen CMV infections were evaluated at the end of treatment: when PCR was still positive either in blood or BAL, CMV infection relapsed within 35+/-5 days; when PCR was negative, CMV infection relapsed after 142+/-57 days (P=0.01). CONCLUSIONS: Negative CMV detection by PCR strongly advocates against a forthcoming CMV infection. PCR assay seems to be a good predictor for early recurrence of CMV infection, and would be useful for monitoring the response to antiviral therapy.

Failure of ganciclovir treatment associated with selection of a ganciclovir-resistant cytomegalovirus strain in a lung transplant recipient.

We report the case of a lung transplant recipient with progressive cytomegalovirus (CMV) disease due to a resistant CMV strain emerging under ganciclovir (GCV) therapy. A discriminative polymerase chain reaction (PCR) assay, designed to detect the resistance-related V460 mutation within the viral enzyme UL97, revealed the presence of a mutated strain in a heterogeneous isolate 51 days after transplantation. The conventional antiviral susceptibility assay had failed to demonstrate resistance to GCV. Under prolonged GCV therapy, the mutated strain dominated the wild-type strain, as shown by the PCR assay. This domination led to laboratory resistance, associated with recurrent fever and progressively severe retinitis. As this discriminative PCR assay was shown to be effective in detecting mutated strains that constitute a minority in the virus load, it should allow better management of patients with CMV disease.

Blood and alveolar lymphocyte subsets in pulmonary cytomegalovirus infection after lung transplantation.

BACKGROUND: Cytomegalovirus (CMV) pneumonitis has been shown to be associated with lymphocytic alveolitis after lung transplantation. In the present study, we investigated a series of bronchoalveolar (BAL) and blood samples, collected in the absence of rejection or acute infectious episodes. in order -1: to evaluate intra-alveolar cell population changes concomitant with CMV replication and -2: to reappraise the value of cell population analysis in the management of patients after lung transplantation. METHODS: We used flow cytometry to investigate modifications of lymphocyte subpopulations related to pulmonary cytomegalovirus infections in blood and BAL samples from a series of 13 lung transplant recipients. After exclusion of samples obtained during pulmonary rejection, bronchiolitis obliterans or acute bacterial infection, 48 blood and BAL samples were retained for analysis: 17 were CMV positive by shell-vial assay and 31 were CMV negative in blood and BAL. RESULTS: Our results demonstrate that pulmonary CMV infection is associated with a significant increase in the total lymphocyte population in BAL samples, but with minor modifications of the various lymphocyte subpopulations and a significantly higher absolute number of B lymphocytes in blood samples. CONCLUSIONS: Cytomegalovirus pulmonary infection is accompanied by only minor changes in BAL lymphocyte subpopulations. The study of BAL lymphocyte subpopulations therefore appears to be of limited clinical value in the diagnosis of pulmonary CMV infection. However, increased blood B-lymphocytes seems to be a clinical feature associated with CMV infection.

[Mucoviscidosis in adults]. / La mucoviscidose de l'adulte.

FROM CHILDREN TO ADULTS: Mucoviscidosis, a genetic autosomal recessive disease, is not only a paediatric disease, but with the progress in therapy, has become a disease of adults. Today, median survival of patients is of 30 years and, in France, more than one third of patients are adults. CLINICAL SYMPTOMS IN ADULTS: Are predominantly respiratory, with dilatation of the bronchi and characteristic colonization flora. Chronic bronchial Pseudomonas aeruginosa colonisation is frequently encountered in adults. It develops in successive episodes towards chronic respiratory failure. Other than this typical form, diagnosed in the first years of life, the discovery of the CFTR (Cystic Fibrosis Transmembrane conductance Regulator) gene and its mutations permits diagnosis of mucoviscidosis in patients presenting with mild, or even monosymptomatic forms of the disease. Today, diagnosis of mucoviscidosis relies on the association of characteristic organ damage and an abnormality in CFTR (sweat test and/or difference in nasal potential) or the revelation of gene mutations on each allele. REGARDING TREATMENT: Respiratory failure is the core of daily therapeutic efforts. Respiratory physical therapy, effort re-education and muscle exercising are essential. Antibiotherapy is aimed at treating, spacing out or preventing the infectious exacerbations, in order to stall the functional degradation. Repeated, sequential cycles of intravenous infusions of antibiotics are required in P. aeruginosa chronic bronchial colonization. Treatment of the primary pyocyanic colonisation and inhaled antiobiotherapy appear promising. Pulmonary transplantation is a recognized and efficient therapeutic in advanced stages of respiratory failure. The discomfort and time the patient has to spend on daily treatments requires regular monitoring, to improve compliance and to improve the quality of life of these patients.

[Lung transplantation in cystic fibrosis in adults. Patient selection criteria]. / Transplantation pulmonaire dans la mucoviscidose de l'adulte. Recommandations pour la sélection des candidats.

Lung transplantation (LT) became during the ten past years an important therapeutic option for cystic fibrosis adult patients with end-stage chronic lung disease. LT clearly improves both survival and long term quality of life. A rigorous selection of the candidates is of paramount importance to improve the results of LT because of the lack of shortage of organs. This selection requires a multidisciplinary assessment to refuse patients with absolute exclusion criteria or general medical conditions that impact negatively on short- and long-term outcome. One of the major difficulties is to determine the best time to refer patients to transplantation, arguing the comparison between the predicted survival time of the candidate, under optimal medical therapy, with or without LT. The selection period is also an active process to prepare the patients to the postoperative follow-up and includes a nutritional and rehabilitation program with an educational and psychological preparation. The aim of the present work is to gather the worldwide principles of the selection of the CF patients for LT, commonly used by the LT centers. These recommendations should provide the CF center practitioners with the main elements to prepare their patients to an LT project before a relentless end-stage clinical condition.

[Bone mineral density in patients with chronic lung diseases]. / Etude de la densité minérale osseuse chez des patients insuffisants respiratoires chroniques.

PURPOSE: We evaluated bone mineral density and phosphorus calcium status in patients with chronic lung diseases. PATIENTS AND METHODS: A prospective study was conducted in 58 patients (43 men and 15 women, mean age 44 years, age range 16-68 years) who were classed in three groups: chronic obstructive diseases (25 patients), cystic fibrosis (19 patients), and other lung diseases (14 patients). Fifteen percent of the patients were receiving corticosteroid therapy. Bone mineral density of the lumbar spin and the femoral neck was measured. RESULTS: Serum calcium, phosphate, creatinine, osteocalcin and parathyroid hormone were normal. The 25-hydroxyvitamin D (normal=9-40 ng/ml) level was in the lower limits of normal (12 ng/ml) and was severely decreased in 12 patients (<7 ng/ml). CONCLUSION: Chronic lung disease can lead to osteoporosis. Corticosteroids, low vitamin D level, sedentary lifestyle, smoking, and in cystic fibrosis nutritional deficiencies, delayed puberty and hypogonadism are risk factors. Bone density must be measured in order to prevent and treat osteoporosis.

[Specific aspects and care of lung involvement in adults with cystic fibrosis]. / Spécificités et prise en charge de l'atteinte pulmonaire au cours de la mucoviscidose à l'âge adulte.

Respiratory impairment is present in almost all adult cystic fibrosis patients and makes the prognosis. Viscous, infected and abundant secretions, inflammation and bronchial oedema, bronchoconstriction and respiratory muscle fatigue lead to airway obstruction, bronchiectasis and respiratory failure. The disease is preferentially located in the upper lobes. Exacerbations of the disease are due to bronchial infections and are often responsible for drops of the respiratory function. Regular spirometric surveillance is fundamental for the prognosis and the assessment of the effects of the treatment. Among adult patients chronic colonisation with mucoid and often multiresistant strains of Pseudomonas Aeruginosa are common. It is treated with i.v. high doses antibiotic courses and nebulized antibiotics between i.v. courses. Respiratory failure may require long term oxygen and non invasive mechanical ventilation. Systemic hypervascularization around the bronchiectasis may lead to moderate to severe hemoptysis, which may require embolization. Pneumothorax are associated with poor prognosis and are treated by pleural drainage and if failure by thoracoscopy.

[Reduction of native lung volume after single-lung transplantation for emphysema]. / Réduction de volume du poumon natif après transplantation unipulmonaire pour emphysème.

We report three cases of volume reduction surgery in three single lung transplant recipients with emphysema. Each patient had a late decline in lung function with hyper-inflation of the native lung. Lung function was improved post-operatively for two patients. The relief of thoracic overdistension may be considered in single lung transplant recipients who exhibit clinical significant functional deterioration.